1. Field of the Invention
This invention relates to a stereo-controlled process for producing 3-beta hydrogen (3R) 4-aroyloxy azetidinone intermediates in high yield having desired chirality which are essential in carbapenem synthesis.
2. Brief Description of Disclosures in the Art
Carbapenem antibiotics, particularly thienamycin and imipenem (see U.S. Pat. Nos. 3,950,377 and 4,194,047) are well known for treating a broad spectrum of gram-negative and gram-positive bacterial infections.
Processes for synthesis of these type antibacterial agents are well known in the art as witness the following patents issued inter alia to Merck & Co.; U.S. Pat. Nos. 4,543,257, 4,234,596 and 4,232,030.
In order to develop, faster, less expensive and better methods for their production, research is continually being carried out in this area. One focus in this field has been on the ketene-imine cycloaddition mode of synthesis of the starting azetidinone intermediates. Particularly desired is a process which produces the initial azetidinone intermediate having a 3-beta hydrogen in high yields. (See following Structure III having a 3-position beta hydrogen. According to the commonly used R/S stereochemical designations, when A in Structure III is aryl, the 3-position is (3S) and when A is aroyloxy, it is (3R), in which the 3-hydrogen remains in the beta stereoconfiguration.)
The cycloaddition of an imine and a ketene to product azetidinones is known in the art, e.g. H. Staudinger and S. Jologin, Chem. Ber., 1911, 44 p. 373.
Recently there has been considerable interest in ketene-imine cycloaddition chemistry in the use of .beta.-hydroxybutyric acid as a readily available, chiral starting material. This reagent has been used in enolate condensations with imines to generate .beta.-lactam intermediates; however, these approaches typically provide modest yields of condensation products and require extensive functional group manipulation in order to liberate the desired C-4 acetoxy azetidinone species, a functionality necessary for rapid conversion to useful carbapenems. See Georg, G.I., Kant, J., Gill, H.S., J. Am. Chem. Soc. 1987, 109, 1129; Hart, D.J., Ha, D.C., Tetrahedron Lett. 1985, 5493; Iimori, T., Shibasaki, M., Tetrahedron Lett. 1985, 1523; Giuanti, G., Narisano, E., Banfi, L., Tetrahedron Lett. 1986, 5955; Ohasi, T., Kan, K., Sada, I., Miyama, A., Watanabe, K., Eur. Pat. Appln. EP 167155. 1986; Aizpurya, J.M., Cossio, F.P., Lecea, B., Palomo, C., Tetrahedron Lett. 1986, 4359; Alcaide, B., Dominguez, G., Escobar, G., Parreno, V., Plumet, J., Heterocycles 1986, 24. 6; and Bose, A.K., Krishnan, L., Wagle, D.R., Manhas, M.S., Tetrahedron Lett. 1986, 5955. The above references are hereby incorporated by reference.
What is desired in the art is a process for producing 3-beta hydrogen (3S)-3-(1-hydroxylethyl)-4-aroyl azetidinones in high yield.